While approximately 60% of depressed patients experience an antidepressant response after sleep deprivation (SD), the clinical utility of this intervention has been limited by the fact that most patients relapse after a night of recovery sleep. The purpose of these studies was to test two possible clinical applications of SD: (1) its ability to hasten the onset of action of antidepressant medication, and (2) its ability to potentiate the action of antidepressant medication in partially-responsive patients. Because patients cannot be blind to the fact that they are being sleep-deprived, it is difficult to design an adequate control condition for SD. The literature indicates that SD in the second half of the night (late SD, or LSD) is a more effective treatment than SD in the first half of the night (early SD, or ESD). Thus, these experiments also tested the utility of using ESD as a control condition for LSD. Patients in both protocols were randomly assigned to ESD or LSD, and followed that schedule of SD for two nights in a row during each of two successive weeks. There was extensive, systematic monitoring of mood and behavior prior to the SD, and for three weeks after the last SD. In the first protocol, patients were drug-free at the beginning of the study, and were started on fluoxetine 20mg qd four days before their first night of SD. Twenty-four patients completed the protocol, eleven in the LSD condition and thirteen in the ESD condition. There are no significant differences between the ESD group and the LSD group in the course of their response to fluoxetine. Thus, while patients improved significantly over the course of the study, it was impossible to distinguish the relative contributions of fluoxetine, SD, and patient expectations to this clinical change. At this point there is no indication that SD can be used to hasten the onset of action of fluoxetine. All patients accepted in the second protocol had been on a stable regimen of antidepressant medication for at least eight weeks, and they were continued on this regimen throughout the study. Twenty-six patients completed this protocol, fourteen in the ESD condition and twelve in the LSD condition. There were no significant differences in the response of the two groups, so ESD does not appear to be an adequate control condition for LSD in this population. However, the SD treatment did appear to decrease significantly the subjects' Hamilton Depression Rating Scale scores. This effect remained significant even after patients whose scores dropped 30% or more upon entry into the study (so-called "placebo responders") were excluded. Therefore, it appears that SD may potentiate the efficacy of antidepressant medications. Prolactin, cortisol, TSH and fT3 levels drawn at 8:00 a.m. at baseline and on the mornings after SD varied significantly over the course of the study but were not related to clinical response.